Indwelling vascular and urinary catheters are becoming essential in the management of hospitalized patients. Implanted orthopedic devices are also becoming more prevalent, partly to meet the needs of a growing elderly population. The benefit derived from these catheters and orthopedic devices, as well as other types of medical devices is often offset by infectious complications.
The most common hospital-acquired infection is urinary tract infection (UTI). The majority of cases of UTI are associated with the use of urinary catheters, including transurethral foley, suprapubic and nephrostomy catheters. These urinary catheters are inserted in a variety of populations, including the elderly, stroke victims, spinal cord-injured patients, post-operative patients and those with obstructive uropathy. Despite adherence to sterile guidelines for the insertion and maintenance of urinary catheters, catheter-associated UTI continues to pose a major problem. For instance, it is estimated that almost one-quarter of hospitalized spinal cord-injured patients develop symptomatic UTI during their hospital course. Gram-negative bacilli account for almost 60-70%, enterococci for about 0.25% and Candida species for about 10% of cases of UTI.
Colonization of bacteria on the surfaces of the implant or other part of the device can produce serious patient problems, including the need to remove and/or replace the implanted device and to vigorously treat secondary infective conditions. A considerable amount of attention and study has been directed toward preventing such colonization by the use of antimicrobial agents, such as antibiotics, bound to the surface of the materials employed in such devices.
Various methods have previously been employed to contact or coat the surfaces of medical devices with an antimicrobial agent. For example, one method would be to flush the surfaces of the device with an antimicrobial containing solution. Generally, the flushing technique would require convenient access to the implantable device. For example, catheters are generally amenable to flushing with a solution of rifampin and minocycline or rifampin and novobiocin. For use in flushing solutions, the effective concentration of the antibiotic would range from about 1 to 10 mg/ml for minocycline, preferably about 2 mg/ml; 1 to 10 mg/ml for rifampin, preferably about 2 mg/ml; and 1 to 10 mg/ml for novobiocin, preferably about 2 mg/ml. The flushing solution would normally be composed of sterile water or sterile normal saline solutions.
A known method of coating the devices is to first apply or absorb to the surface of the medical device a layer of tridodecylmethyl ammonium chloride (TDMAC) surfacant followed by an antiobiotic coating layer. For example, a medical device having a polymeric surface, such as polyethylene, silastic esaltomers, polytetrafluoroethylene or Dacron, can be soaked in a 5% by weight solution of TDMAC for 30 minutes at room temperature, air dried, and rinsed in water to remove excess TDMAC. Alternatively, TDMAC precoated vascular catheters are commercially available. The device carrying the absorbed TDMAC surfactant coating can then be incubated in an antibiotic solution for up to one hour or so, allowed to dry, then washed in sterile water to remove unbound antibiotic and stored in a sterile package until ready for implantation. In general, the antiobiotic solution is composed of a concentration of 0.01 mg/ml to 60 mg/ml of each antiobiotic in an aqueous pH 7.4-7.6 buffered solution, sterile water, or methanol. According to one method, an antibiotic solution of 60 mg of minocycline and 30 mg of rifampin per ml of solution is applied to the TDMAC coated catheter.
Another successful coating method is impregnation of an antimicrobial agent. The antimicrobial agent penetrates and is incorporated in the exposed surfaces. The antimicrobial composition is formed by dissolving an antimicrobial agent in an organic solvent, adding a penetrating agent, and adding an alkalinizing agent to the composition. The composition is heated to a temperature between 30° C. and 70° C. prior to applying to the medical device. See, e.g., U.S. Pat. No. 5,902,283 and U.S. Pat. No. 5,624,704.
A further method known to coat the surface of medical devices with antiobiotics involves first coating the selected surfaces with benzalkonium chloride followed by ionic bonding of the antiobiotic composition. See, e.g., Solomon, D. D. and Sherertz, R. J., J. Controlled Release, 6:343-352 (1987) and U.S. Pat. No. 4,442,133.
These and many other methods of coating medical devices with antibiotics appear in numerous patents and medical journal articles. Practice of the prior art coating methods results in a catheter or medical device wherein only the surface of the device is coated with an antibiotic. While the surface coated catheter does provide effective protection against bacteria initially, the effectiveness of the coating diminishes over time. During use of the medical device or catheter, the antimicrobials leach from the surface of the device into the surrounding environment. Over a period of time, the amount of antibiotics present on the surface decreases to a point where the protection against bacteria is no longer effective.
Previously there have been several approaches to prophylaxis of urinary tract infection in chronically catheter dependent patients. Antibacterial compounds applied at the urethral meatus, silver impregnated catheters, intravesical instillation of various chemicals and antimicrobial agents, such as methenamine, cranberry juice and ascorbic acid, have been used with mixed success at best. Prophylactic oral antibiotics may reduce the incidence of asymptomatic bacteruria in patients on clean intermittent catheterization but do not reduce that of symptomatic infection. A prospective study found a higher incidence of symptomatic infection among patients who received prophylactic antibiotics. Furthermore, prolonged treatment with antimicrobial agents, creates drug resistant pathogens, breakthrough infections and disruption of the normal flora.
With the world wide emergence of increased antibiotic resistant agents, an interest has developed in the use of bacterial interference as a means to cope with this problem. In nature, bacteria interact with each other as they attempt to establish themselves and dominate their environment. Some of the interactions are synergistic, whereas others are antagonistic. It has been suggested that these antagonistic interactions, so-called bacterial interference, may act in the prevention of certain infectious diseases. Bacterial interference operates through several mechanisms, i.e., production of antagonistic substances, changes in the bacterial microenvironment, and reduction of needed nutritional substances. Typically, the therapeutic approach of using bacterial interference involves the implantation of low-virulence bacterial strains that are potentially capable of interfering with the colonization and infection of more virulent microorganisms.
In recent years, the use of Lactobacillus has been investigated as a possible treatment for UTI. It is well known that indigenous, non-pathogenic bacteria predominate on intestinal, vaginal and uro-epithelial cells and associated mucus in the health state, and that pathogenic organisms (such as bacteria, yeast and viruses) predominate in the stages leading to and during infections. Organisms such as Escherichia coli, enterococci, Candida, Gardnerella and Klebsiella originate from the bowel, colonize the perineum, vagina, urethra and can infect the bladder and vagina. See e.g., U.S. Pat. No. 5,645,830 and U.S. Pat. No. 6,004,551.
In addition to the increased risk of infection associated with the use of urinary catheters, these patients are subjected to an increase in medical expenses. Typically, urinary catheters are replaced every 2-4 weeks. This time frame was established by the medical community based upon the safety concern of a biofilm of pathogenic bacteria developing on the catheter surface. Thus, patients may need to schedule an appointment every 2-4 weeks to have the catheter replaced resulting in the expense of office visits and the cost of approximately 24 catheters per year.
There is a general appreciation in the medical community that better methods to prevent the development of urinary catheter-associated UTI are needed. This invention describes for the first time the use of a non-pathogenic bacterium in combination with an antimicrobial agent to prevent UTI. It is noteworthy that the non-pathogenic bacterium used in this invention had been previously considered a pathogenic bacterium that results in UTI, thus suggesting, that this invention is indeed non-obvious.
Furthermore, this invention addresses the long-felt need of reducing the medical expenses incurred by patients that require a urinary catheter. Coating a urinary catheter with both an antimicrobial agent and a non-pathogenic bacterium will prolong the time frame between replacements of catheters. This invention could potentially increase the time from 2-4 weeks up to several months, thus, the amount of catheters and incurred medical expenses are reduced.